This application is a 371 of PCT/JP98/04757 filed on Oct. 21, 1998.
1. Technical Field
The present invention relates to a preparation of irrigating solution for ocular surgery which may be used in the surgery of cataract, intraocular lens transplantation or glaucoma. More specifically, it relates to a preparation of irrigating solution which is suitable for protecting intraocular tissues, removing the substances left in the eye after the surgery by suction and preventing the surface of the corneal epithelium and the conjunctiva from drying in order to perform the surgery safely and effectively.
2. Background Art
Recently, development of ocular surgery methods for surgery of cataract, intraocular lens transplantation, glaucoma and the like has remarkably progressed. An irrigating solution which is used as a surgical adjuvant plays an important role in order to perform the above surgery safely and effectively. For example, when the periphery of the cornea is incised by a scalpel at the start of the surgery of cataract, the aqueous humor flows out from the anterior chamber immediately. Therefore, injection of an irrigating solution and a viscoelastic substance is indispensable for protecting intraocular tissues and cells and for maintaining the space of the anterior chamber. Further, when the irrigating solution is present in the eye at the time of breaking the opaque crystalline lens into pieces and extracting them, the pieces can be removed smoothly by suction. The irrigating solution is also used for preventing the surfaces of the cornea and the conjunctiva from drying during operation.
Some important points in the preparation for achieving such application purposes of the irrigating solution are as follows: (1) the osmotic pressure and pH of the preparation must be physiologically harmonized with the intraocular tissues and the corneal endothelial cell; 2) the essential compounds of aqueous humor components such as inorganic salts, energy sources and cell-activators must be added; 3) the preparation must be biologically safe; and 4) the preparation must be able to be preserved at room temperature for the long term.
One of preparation of irrigating solution for ocular surgery which are currently available in Japan""s market is a commercial product containing oxyglutathione as a cell-activator, and another commercial product having a bicarbonate ion-based buffer system has already been practically used. However, since these are a two-pack preparation which requires two types of solutions to be mixed prior to use or a preparation which contains no ingredients effective for protecting the corneal endothelial cell, they have not a few problems to be solved with regard to stability, simplicity at the time of use and efficacy as a preparation.
A preparation of irrigating solution for ocular surgery which is composed essentially of 3-hydroxybutyric acid as an energy source is disclosed in the specifications of U.S. Pat. Nos. 5,116,868 and 5,298,487. However, the preparations described in the specifications do not contain bicarbonate ions necessary to sustain the function of the corneal endothelial cell. The disclosed reasons why the preparation does not have to contain the bicarbonate ions in advance are that when the bicarbonate ions exist in the preparation, the pH of the preparation fluctuates due to a CO2 partial pressure, whereby the preparation becomes unstable, and that 3-hydroxybutyric acid generates CO2 through metabolism and the CO2 changes into the bicarbonate ions which are therefore supplied automatically. In addition, sodium acetate, which is generally said to be absent in human aqueous humor, is contained in the above preparation.
D-3-hydroxybutyric acid or its salts used as active ingredients in the present invention are known to be biological substances existing in humans and most of other mammals, biosynthesized through an oxidation process of fatty acids in the liver, and carried into the cornea as well as peripheral tissues out of the liver by blood to be utilized as an efficient energy source (refer to Lehninger, New Biochem., 2nd Ed., p625, 1993 and NATURE, No.4, 841, p597, 1962). It is also known that the substances are much more useful for corneal tissues as an energy source than glucose (refer to TRANSPLANTATION, 57, p1778-1785, 1994).
D-3-hydroxybutyric acid or its salts are oxidized in the TCA cycle of these tissues to produce ATP and are eventually converted into carbon dioxide and water (refer to NATURE, No.4841, p597, 1962).
As for the application of D-3-hydroxybutyric acid and its salts to drugs, it has been reported that they are mixed into an infusion solution for supplying nutrients to patients in the accelerated state as to biological protein catabolism or those having an invaded body (refer to Japanese Patent Application Laid-Open No. 191212/1990).
It is disclosed in GANKA RINSHO IHO, Vol.92, No.7 (1998), p902-905, that the influence of an intraocular irrigating solution containing xcex2-hydroxybutyrate on the retinas has been studied on an electroretinogram (ERG) using the retinas extracted from rabbits and that the intraocular irrigating solution sustains retinal functions which are equal to or more than the market product BSS PLUS (registered trademark) does. However, the D-form of xcex2-hydroxybutyrate is not disclosed in this report, and only the influence of xcex2-hydroxybutyrate on the retinas is disclosed.
In addition, the Proceeding 201 of the 36th Meeting of the Retina Vitreous Society of Japan held on Jul. 24-26, 1997, discloses that the influence of a newly formulated intraocular irrigating solution containing sodium D-xcex2-hydroxybutyrate on the retinas was studied on an ERG using the retinas extracted from rabbits and that the newly formulated intraocular irrigating solution could sustain the ERG of a retinal in vitro sample which is equal to or more than BSS PLUS does.
However, the detailed composition of the above irrigating solution is not disclosed in this report, and only its influence on the retinas is disclosed.
It is an object of the present invention to provide a one-pack preparation of irrigating solution for ocular surgery of cataract, glaucoma or intraocular lens transplantation, which is excellent in the protection of ophthalmic tissues and endothelial cells during and after the operation and has a high in vivo stability.
It is another object of the present invention is to provide an intraocular preparation of irrigating solution having formulation stability in addition to the above excellent properties by adding inorganic ions, energy sources, isotonic agents, buffers, bicarbonate ions and stabilizers.
Other objects and advantages of the present invention will become apparent from the following description.
According to the present invention, the above objects and advantages can be attained by a one solution-pack preparation of irrigating solution for ocular surgery of cataract, glaucoma or intraocular lens transplantation, which comprises an aqueous solution containing:
(1) at least 0.1 mM but less than 500 mM of at least one compound selected from the group consisting of D-3-hydroxybutyric acid and water-soluble salts thereof as a D-3-hydroxybutyrate anion;
(2) at least 0.1 mM but less than 100 mM of water-soluble bicarbonate salts as a bicarbonate ion;
(3) at least 0.1 mM but less than 50 mM of at least one compound selected from the group consisting of phosphoric acid and water-soluble phosphate salts thereof as a phosphate ion;
(4) at least 0.01 mM but less than 50 mM of water-soluble calcium salts as a calcium ion; and
(5) at least 0.01 mM but less than 50 mM of water-soluble magnesium salts as a magnesium ion.